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Advisory Committee Chair

Steven M Rowe

Advisory Committee Members

J E Blalock

James F Collawn

Robinna G Lorenz

S V Raju

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Chronic obstructive pulmonary disease (COPD), characterized by progressive loss of lung function including mucus obstruction and airway remodeling, is primarily caused by cigarette smoking. This pulmonary phenotype resembles that of cystic fibrosis (CF), which results from genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel important in maintaining airway surface hydration and mucus clearance. Cigarette smoke exposure has been found to induce acquired CFTR dysfunction, leading to airway dehydration, abnormal mucin production, and impaired mucus transport. Smoke exposure also induces mucus hypersecretion and ciliary dysfunction; together, these changes result in defective mucus clearance and subsequent muco-obstruction. E-cigarettes, a popular alternative to traditional cigarettes, are commonly perceived to be safer than smoking. However, evidence has shown that e-cigarette components and vapor can cause defects in the airways similar to tobacco smoke. Thus, we hypothesized that e-cigarette use can induce acquired CFTR dysfunction in a similar manner to cigarette smoking, which may contribute to COPD pathogenesis. We demonstrate that e-cigarette vapor not only induces acquired CFTR dysfunction, but it also contains respiratory toxicants known to impair CFTR activity, suggesting that e-cigarettes may still lead to pulmonary decrements with chronic use. Additionally, muco-obstruction paired with observations of mucus abnormalities in CF and cigarette smoke-induced acquired CFTR dysfunction, led to the hypothesis that cigarette smoke exposure alters the airway functional microanatomy and mucus viscoelasticity, contributing to mucus transport decrements. Using real-time imaging that allows co-localized measures of the mucociliary transport (MCT) apparatus in conjunction with a novel COPD animal model, we establish that chronic smoke exposure impairs MCT in a manner that is dependent on the functional microanatomy as well as mucus properties. Here, we provide evidence that cigarette alternatives can induce airway epithelial ion transport defects that may contribute to COPD pathogenesis, and that mucociliary dysfunction and mucus abnormalities are important in COPD. Based on our data, augmenting secretion by way of CFTR channel activation or by cholinergic stimulation may improve ion transport and overcome airway surface dehydration and MCT decrements, respectively; these, along with muco-active agents to reduce mucus viscoelasticity, are promising therapeutic avenues for slowing COPD progression.

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